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J. Exp. Med.,
Volume 187, Number 5, March 2, 1998 663-674
B1 (NF-
B1) Transcription Factors to Regulate Cell
Cycle Progression and Apoptosis in Quiescent and
Mitogen-activated Cells
By

From * The Walter and Eliza Hall Institute of Medical Research, Post Office The Royal Melbourne
Hospital, Victoria 3050, Australia; the Rel and nuclear factor (NF)-
Department of Immunology, Saga Medical School,
Nabeshima, Saga 849, Japan; and the § University of California, Berkeley, California 94720
B1, two members of the Rel/NF-
B transcription factor family,
are essential for mitogen-induced B cell proliferation. Using mice with inactivated Rel or NF-
B1 genes, we show that these transcription factors differentially regulate cell cycle progression and
apoptosis in B lymphocytes. Consistent with an increased rate of mature B cell turnover in naive
nfkb1
/
mice, the level of apoptosis in cultures of quiescent nfkb1
/
, but not c-rel
/
, B
cells is higher. The failure of c-rel
/
or nfkb1
/
B cells to proliferate in response to particular
mitogens coincides with a cell cycle block early in G1 and elevated cell death. Expression of a bcl-2
transgene prevents apoptosis in resting and activated c-rel
/
and nfkb1
/
B cells, but does
not overcome the block in cell cycle progression, suggesting that the impaired proliferation is not
simply a consequence of apoptosis and that Rel/NF-
B proteins regulate cell survival and cell cycle
control through independent mechanisms. In contrast to certain B lymphoma cell lines in which
mitogen-induced cell death can result from Rel/NF-
B-dependent downregulation of c-myc, expression of c-myc is normal in resting and stimulated c-rel
/
B cells, indicating that target
gene(s) regulated by Rel that are important for preventing apoptosis may differ in normal and immortalized B cells. Collectively, these results are the first to demonstrate that in normal B cells,
NF-
B1 regulates survival of cells in G0, whereas mitogenic activation induced by distinct stimuli
requires different Rel/NF-
B factors to control cell cycle progression and prevent apoptosis.
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